Molecular target-based cancer therapy is playing a more and more important role in cancer therapy because of its high specificity, good tolerance and so on. There are different kinds of molecular targeted drugs such as monoclonal antibodies and small molecular kinase inhibitors, and more than 50 drugs have been approved since 1997. When the first monoclonal antibody, rituximab, was on the market. The development of molecular target-based cancer therapeutics has become the main approach. Based on this, we summarized the drugs approved by FDA and introduced their mechanism of actions and clinical applications. In order to incorporate most molecular targeted drugs and describe clearly various characteristics, we divided them into four categories: drugs related to EGFR, drugs related to antiangiogenesis, drugs related to specific antigen and other targeted drugs. The purpose of this review is to provide a current status of this field and discover the main problems in the molecular targeted therapy.
Angiogenesis Inhibitors ; Antibodies, Monoclonal ; Drug Delivery Systems ; Humans ; Molecular Targeted Therapy ; Neoplasms ; drug therapy ; Protein Kinase Inhibitors ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors

The tube formation assay is a widely used in vitro experiment model to evaluate angiogenic properties by measuring the formation of tubular structures from vascular endothelial cells (ECs). in vitro experimental results are crucial when considered the advisability of moving forward to in vivo studies. Thus, the additional attentions to the in vitro assay is necessary to improve the quality of the pre-clinical data, leading to better decision-making for successful drug discovery. In this study, we improved the tube formation assay system in three aspects. First, we used human endothelial colony forming cells (ECFCs), which are endothelial precursors that have a robust proliferative capacity and more defined angiogenic characteristics compared to mature ECs. Second, we utilized a real-time cell recorder to track the progression of tube formation for 48 hours. Third, to minimize analysis error due to the limited observation area, we used image-stitching software to increase the microscope field of view to a 2×2 stitched area from the 4× object lens. Our advanced tube formation assay system successfully demonstrated the time-dependent dynamic progression of tube formation in the presence and absence of VEGF and FGF-2. Vatalanib, VEGF inhibitor, was tested by our assay system. Of note, IC₅₀ values of vatalanib was different at each observation time point. Collectively, these results indicate that our advanced tube formation assay system replicates the dynamic progression of tube formation in response to angiogenic modulators. Therefore, this new system provides a sensitive and versatile assay model for evaluating pro- or anti-angiogenic drugs.
Angiogenesis Inhibitors ; Attention ; Drug Discovery ; Endothelial Cells ; Fibroblast Growth Factor 2 ; Humans* ; In Vitro Techniques* ; Vascular Endothelial Growth Factor A

AIM: To investigate the chemical constituents and their biological activities of the aerial parts of Euphorbia tibetica. METHOD: Compounds were isolated and purified by various chromatographic methods, and their structures were elucidated through the use of extensive spectroscopic techniques including 2D-NMR, the structures of compounds 5 and 6 were confirmed by single-crystal X-ray crystallography. Bioactivities of all the isolated compounds were evaluated by the MTT method on A549 and anti-angiogenesis assay. RESULTS: One new compound, methyl 4-epi-shikimate-3-O-gallate (1), together with twenty-three known constituents (2-24) were isolated from the aerial parts of E. tibetica. CONCLUSION Compound 1 is new, and the other compounds were isolated from this plant for the first time. Compounds 5-7, 9, 11, 17, 18 and 20 exhibited inhibitory effects on the growth of human lung cancer cell A549 and compounds 5, 7, 12, 13, 17 and 19 showed anti-angiogenic effects in a zebrafish model.
Angiogenesis Inhibitors ; chemistry ; pharmacology ; Animals ; Cell Line ; Cell Proliferation ; drug effects ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; Euphorbia ; chemistry ; Growth Inhibitors ; chemistry ; pharmacology ; Humans ; Molecular Structure ; Zebrafish

5-Fluorouracil (5-FU) has been the main chemotherapeutic agent for the treatment of colorectal cancer for four decades with modest efficacy. Modulation of 5-FU by leucovorin or continuous infusion improves the response rate, but overall survival duration remains approximately 12 months. Many oral fluoropyrimidines have been studied, including capecitabine, UFT, S-1, and Eniluracil. Capecitabine has demonstrated equivalent efficacy with 5-FU and has been approved as first line treatment. CPT-11 demonstrated non-crossover resistance with 5-FU and was proven to be effective treatment for patients who received prior 5-FU. CPT-11 in combination with 5-FU has demonstrated improved response rate and overall survival duration over 5-FU or CPT-11. Oxaliplatin plus 5-FU has offered another effective treatment option for colorectal cancer. Both 5-FU plus leucovorin in combination with CPT-11 or oxaliplatin are widely used first-line chemotherapies for advanced colorectal cancer. The combinations of capecitabine with CPT-11 or oxaliplatin are being developed. Several molecular targeting agents such as EGFR inhibitors and antiangiogenic agents have developed. Cetuximab induces a broad range of cellular responses in tumors expressing EGFR, enhancing sensitivity to radiotherapy and chemotherapeutic agents. A key angiogenic pathway in the stimulation of tumour growth is the vascular endothelial growth factor (VEGF) pathway, inhibited by the monoclonal antibody bevacizumab. Phase II first line and phase III second line studies of oxaliplatin in combination with bevacizumab are now in progress. Optimal combinations and sequences of treatment are being studied, since several effective regimens have become available.
Angiogenesis Inhibitors ; Colorectal Neoplasms* ; Drug Therapy* ; Fluorouracil ; Humans ; Leucovorin ; Radiotherapy ; Vascular Endothelial Growth Factor A ; Bevacizumab ; Capecitabine ; Cetuximab

PURPOSE: Ticlopidine, which has platelet inhibitory property, is currently used in peripheral arterial obstructive disease, ischemic stroke, and coronary artery disease. It is also known to have antiangiogenesis effect. We studied the effect of ticlopidine on rabbit corneal angiogenesis induced by VEGF. METHODS: In control group, a hydron pellet containing 300ng VEGF and phosphate buffered saline(PBS) was implanted intrastromally in the superior cornea. In treatment group, a hydron pellet containing 300ng VEGF and 375micro gram ticlopidine was implanted as the same manner. At 3, 5, and 7 day after implantation, we examined corneas under the microscope and estimated the angiogenesis score. RESULTS: At 5 and 7 day after implantation, ticlopidine-treated group had mean angiogenesis score of 27.9 and 49.1(p=0.014, independent t-test), while control group scored 13.0 and 25.3(p=0.004). CONCLUSIONS: In a rabbit corneal pocket assay, ticlopidine appears to have inhibitory effect on VEGF-induced corneal angiogenesis.
Angiogenesis Inhibitors ; Arterial Occlusive Diseases ; Blood Platelets ; Cornea ; Corneal Neovascularization* ; Coronary Artery Disease ; Stroke ; Ticlopidine* ; Vascular Endothelial Growth Factor A*

OBJECTIVETo investigate the effects of two histone deacetylase (HDAC) inhibitors, valproic acid (VPA) and TSA, on the expression of vascular endothelial growth factor (VEGF) and its receptor KDR of the leukemia cell line Kasumi-1 cells, and to explore their potential mechanism in leukemia angiogenesis.

METHODKasumi-1 cells were treated with VPA and TSA at different concentrations for 3 days. The mRNA and protein expression levels of VEGF and KDR were determined by semi-quantitative RT-PCR and Western blot, and the bFGF mRNA by semi-quantitative RT-PCR.

RESULTSAs compared with that of control groups, VPA at 3 mmol/L downregulated the VEGF mRNA expression level for VEGF(121) from 0.632 ± 0.014 to 0.034 ± 0.004 and for VEGF(165) from 0.526 ± 0.021 to 0.015 ± 0.001, for KDR mRNA from 0.258 ± 0.034 to 0.038 ± 0.000, and for bFGF mRNA from 0.228 ± 0.017 to 0.086 ± 0.015. TSA downregulated the VEGF mRNA and KDR mRNA at concentration of 100 nmol/L, but its effect on bFGF mRNA only at higher concentration.

CONCLUSIONHDAC inhibitors might inhibit the leukemia angiogenesis by regulating the expression of VEGF and its recptor.

Angiogenesis Inducing Agents ; Cell Line ; Histone Deacetylase Inhibitors ; pharmacology ; Humans ; RNA, Messenger ; genetics ; Valproic Acid ; pharmacology ; Vascular Endothelial Growth Factor A

BACKGROUND: Angiogenesis plays a key role in the growth and metastasis of solid tumor. But it is not known whether the hematopoietic tumor depends on angiogenesis. To evaluate the prognostic roles of vascular endothelial growth factor (VEGF) expression and angiogenesis in patients with acute myelogenous leukemia, we analyzed the relationships between the level of VEGF expression, microvessel counts (MVC) in the bone marrow specimen of acute myelogenous leukemia patient and remission, relapse, and overall survival. METHODS: We evaluated bone marrow biopsy from 32 adult patients with newly diagnosed acute myelogenous leukemia and 16 controls with normal bone marrow. VEGF expression and MVC were assessed by immunohistochemical stain with monoclonal antibody to VEGF and polyclonal antibody to factor VIIIRAg, respectively. RESULTS: VEGF expression was higher in acute myelogenous leukemia than that of control (56.4+/-32.8% vs 19.0+/-25.9%, P=0.004). MVC was also higher in acute myelogenousleukemia than that of control (14.7+/-10.3 vs 6.2+/-3.8, P<0.001). Between high VEGF expression group and low VEGF expression group, there were no significant differences in the complete remission (CR), relapse and overall survival. There was no significant difference of MVC between CR group and non- CR group. Relapse group tends to have higher MVC than non-relapse group without statistical significance (P=0.06). There were no significant differences of MVC between hypervascular group and hypovascular group in remission, relapse and overall survival. CONCLUSION: In patients with acute myelogenous leukemia, VEGF expression and MVC were significantly higher than those of control. These findings suggest angiogenesis may play an important role in the pathogenesis of acute myelogenous leukemia. But there was no clinical correlation between the level of VEGF expression, MVC and remission, relapse and overall survival in this study. Further study willbe necessary for the establishment of prognostic role of VEGF expression and angioge-nesis and clinical efficacy of angiogenic inhibitors in acute myelogenous leukemia.
Adult ; Angiogenesis Inhibitors ; Biopsy ; Bone Marrow ; Humans ; Leukemia, Myeloid, Acute* ; Microvessels ; Neoplasm Metastasis ; Recurrence ; Vascular Endothelial Growth Factor A*

The present study investigated the mechanism of components in stasis-resolving and collateral-dredging Chinese herbal medicines, including scutellarin(Scu), paeonol(Pae), and hydroxy safflower yellow A(HSYA), in the treatment of psoriasis by regulating angiogenesis and inflammation. The human umbilical vein endothelial cells(HUVECs) cultured in vitro were divided into a normal group, a model group, a VEGFR tyrosine kinase inhibitor Ⅱ(VRI) group, and Scu, Pae, and HSYA groups with low, me-dium, and high doses. Cell viability was detected by the CCK-8 assay. Cell migration was detected by wound healing assay. Tube formation assay was used to measure the tube formation ability. Western blot was used to detect the protein expression of the VEGFR2/Akt/ERK1/2 signaling pathway. The secretion levels of inflammatory cytokines IFN-γ, IL-1β, IL-6, and TNF-α were detected by ELISA. The results showed that compared with the model group, all the Scu, Pae, and HSYA groups could reduce cell viability, inhibit cell migration and tube formation(P<0.05, P<0.01), and down-regulated the protein expression of VEGFR2, p-VEGFR2, Akt, p-Akt, ERK1/2, and p-ERK1/2. Scu and Pae could down-regulate VEGFR2 expression(P<0.05, P<0.01), while other groups only showed a downward trend. Scu and Pae significantly reduced IFN-γ and IL-6 levels(P<0.01), and HSYA significantly reduced the levels of IFN-γ, IL-1β, and IL-6(P<0.01). Scu, Pae, and HSYA had no significant effect on TNF-α. The results suggested that Scu, Pae, and HSYA may exert a therapeutic role in psoriasis-related angiogenesis and inflammation by inhibiting VEGFR2/Akt/ERK1/2 signaling pathway and inhibiting the secretion of IFN-γ, IL-1β, and IL-6.
Angiogenesis Inhibitors/pharmacology* ; China ; Human Umbilical Vein Endothelial Cells ; Humans ; Neovascularization, Pathologic/drug therapy* ; Vascular Endothelial Growth Factor A/metabolism*

Ovarian cancer is one of the three major cancers in gynecology. Ovarian cancer has insidious symptoms in its early stages and mostly has progressed to advanced stages when detected. Surgical treatment combined with chemotherapy is currently the main treatment, but the 5-year survival rate is still less than 45%. Angiogenesis is a key step in the growth and metastasis of ovarian cancer. The inhibition of ovarian cancer angiogenesis has become a new hotspot in anti-tumor targeted therapy, which has many advantages such as less drug resistance, high specificity, few side effects, and broad anti-tumor spectrum. Modern research has confirmed that traditional Chinese medicine(TCM) can inhibit tumor angiogenesis by inhibiting the expression of pro-angiogenic factors, up-regulating the expression of anti-angiogenic factors, inhibiting the proliferation of vascular endothelial cells, reducing the density of tumor microvessels, and regulating related signaling pathways, with unique advantages in the treatment of ovarian cancer. This paper presented a review of the role of TCM in inhibiting ovarian cancer angiogenesis in order to provide references for the optimization of clinical ovarian cancer treatment strategies.
Humans ; Female ; Medicine, Chinese Traditional ; Vascular Endothelial Growth Factor A/metabolism* ; Endothelial Cells/metabolism* ; Angiogenesis ; Angiogenesis Inhibitors/therapeutic use* ; Ovarian Neoplasms/genetics* ; Neovascularization, Pathologic/genetics*

The global burden of advanced stage cervical cancer remains significant, particular in resource poor countries where effective screening programs are absent. Unfortunately, a proportion of patients will be diagnosed with advanced stage disease, and may suffer from persistent or recurrent disease despite treatment with combination chemotherapy and radiation. Patients with recurrent disease have a poor salvage rate, with an expected 5-year survival of less than 10%. Recently, significant gains have been made in the antiangiogenic arena; nonetheless the need to develop effective alternate targeted strategies is implicit. As such, a review of molecular targeted therapy in the treatment of this disease is warranted. In an era of biologics, combined therapy with cytotoxic drugs and molecular targeted agents, represents an exciting arena yet to be fully explored.
Angiogenesis Inhibitors/therapeutic use ; Antineoplastic Agents/*therapeutic use ; Female ; Histone Deacetylase Inhibitors/therapeutic use ; Humans ; Molecular Targeted Therapy/*methods ; Receptor, Epidermal Growth Factor/antagonists & inhibitors ; Salvage Therapy/methods ; Uterine Cervical Neoplasms/*drug therapy